Aromatic metabolic pathways

In man, the metabolic pathways of mepirizole were distinct from those in experimental animals, since hydroxylation on each of the aromatic rings did not occur in man. Compound (752) was obtained by oxidation of the 3-methyl group to the carboxylic acid (a similar process occurs with 5-methylpyrazole-3-carboxylic acid, an active metabolite of 3,5-dimethylpyrazole). However, the carboxylic acid metabolite of mepirizole had no analgesic activity and did not decrease blood glucose. 

Metabolic pathways containing dioxygenases in wild-type strains are usually related to detoxification processes upon conversion of aromatic xenobiotics to phenols and catechols, which are more readily excreted. Within such pathways, the intermediate chiral cis-diol is rearomatized by a dihydrodiol-dehydrogenase. While this mild route to catechols is also exploited synthetically [221], the chirality is lost. In the context of asymmetric synthesis, such further biotransformations have to be prevented, which was initially realized by using mutant strains deficient in enzymes responsible for the rearomatization. Today, several dioxygenases with complementary substrate profiles are available, as outlined in Table 9.6. Considering the delicate architecture of these enzyme complexes, recombinant whole-cell-mediated biotransformations are the only option for such conversions. E. coli is preferably used as host and fermentation protocols have been optimized [222,223]. 

The NHase responsible for aldoxime metabolism from the i -pyridine-3-aldoxime-degrading bacterium, Rhodococcus sp. strain YH3-3, was purified and characterized. Addition of cobalt ion was necessary for the formation of enzyme. The native enzyme had a Mr of 130000 and consisted of two subunits (a-subunit, 27 100 (3-subunit, 34500). The enzyme contained approximately 2 mol cobalt per mol enzyme. The enzyme had a wide substrate specificity it acted on aliphatic saturated and unsaturated as well as aromatic nitriles. The N-terminus of the (3-subunit showed good sequence similarities with those of other NHases. Thus, this NHase is part of the metabolic pathway for aldoximes in microorganisms. 

Breese K, M Boll, J Alt-Mdrbe, H Schaggrer, G Euchs (1998) Genes encoding the benzoyl-CoA pathways of anaerobic aromatic metabolism in the bacterium Thauera aromatica. Eur J Biochem 256 148-154. 

Cain RB, RF Bilton, JA Darrah (1968) The metabolism of aromatic acids by micro-organisms. Metabolic pathways in the fungi. Biochem J 108 797-828. 

The activity of PK and NRPSs is often precluded and/or followed by actions upon the natural products by modifying enzymes. There exists a first level of diversity in which the monomers for respective synthases must be created. For instance, in the case of many NRPs, noncanonical amino acids must be biosynthesized by a series of enzymes found within the biosynthetic gene cluster in order for the peptides to be available for elongation by the NRPS. A second level of molecular diversity comes into play via post-synthase modification. Examples of these activities include macrocyclization, heterocyclization, aromatization, methylation, oxidation, reduction, halogenation, and glycosylation. Finally, a third level of diversity can occur in which molecules from disparate secondary metabolic pathways may interact, such as the modification of a natural product by an isoprenoid oligomer. Here, we will cover only a small subsection of... 

Nitro polycyclic aromatic hydrocarbons are environmental contaminants which have been detected in airborne particulates, coal fly ash, diesel emission and carbon black photocopier toners. These compounds are metabolized Tn vitro to genotoxic agents through ring oxidation and/or nitroreduction. The details of these metabolic pathways are considered using 4-nitrobiphenyl, 1- and 2-nitronaphthalene, 5-nitro-acenaphthene, 7-nitrobenz[a]anthracene, 6-nitro-chrysene, 1-nitropyrene, 1,3-, 1,6- and 1,8-dinitro-pyrene, and 1-, 3- and 6-nitrobenzo[a] pyrene as examples ... 

Karp, J.M., Rodrigo, K.A., Pei, P., Pavlick, M.D., Andersen, J.D., McTigue, D.J., Fields, H.W. and Mallery, S.R. (2005) Sanguinarine activates polycyclic aromatic hydrocarbon associated metabolic pathways in human oral keratinocytes and tissues. Toxicology Letters, 158, 50-60. 

Figure 17.6 Examples of aromatic compounds found in some metabolic pathways...

Preston BD, Miller JA, Miller EC. 1983. Non-arene oxide aromatic ring hydroxylation of 2,2,5,5 -tetrachlorobiphenyl as the major metabolic pathway catalyzed by phenobarbital-induced rat liver microsomes. J Biol Chem 258 8304-8311. 

For these reasons, microbial sensors are less suitable for the determination of individual analytes. However, some practical apphcations for biosensors based on enzymes or antibodies for the specific determination of environmentally relevant compounds can be expected soon [11]. Furthermore, in some cases defined specific metabolic pathways in microorganisms are used, leading to microbial sensors for more selective analysis for those environmental pollutants which cannot be measured by the use of simple enzyme reactions, e.g., aromatic compounds and heavy metals. In this context it is also important to mention the aspect of bio availability, a parameter which is included by the measuring procedure of microbial sensors as an integral effect. 

Microbial sensors are less suitable for the determination of individual analytes. However, in some cases, specific metabolic pathways are used, allowing microbial sensors to be more selective for those xenobiotic compounds, which are not detectable with simple enzyme reactions, e.g., aromatic compounds and... 

Although the two major routes for metabolism of adrenaline and noradrenaline are well established, and involve either methylation of the 3-hydroxyl group on the aromatic nucleus or oxidative deamination (cf. refs. 35, 93, 94, 229-231), the evidence to date does not warrant the complete rejection of a further possible metabolic pathway involving oxidation to an aminochrome (such as adrenochrome or noradrenochrome) in some instances. 

Figure 5.4. Metabolic pathways of polycyclic aromatic hydrocarbon oxidation by white-rot fungi.

Some inborn errors of metabolism can be characterized by excessive urinary excretion of aromatic acid metabolites. These acids are distinct from the vanillyl acids discussed in a previous section. Phenylketonuria, alkaptonuria, and tyrosinosis can be diagnosed by determination of the aromatic acid metabolites. Aromatic acid profiles are characteristic of specific metabolic defects, and can be used to confirm diagnoses obtained from amino acid and other studies. Quantification of the individual aromatic acid gives information as to the fate of ingested amino acid in diseases such as phenylketonuria, where there is a block in the metabolic pathway involving the particular amino acid. 

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